Flashcards in Lecture 9: Glycogen Metabolism Deck (64):
The hormone insulin favors glycogen synthesis by which of the following mechanisms?
A) Promoting the dephospho form of glycogen synthase
B) Promoting the phospho form of glycogen synthase
C) Promoting the phospho form of glycogen phosphorylase
D) Inhibiting the insulin receptor
E) Acivating glycogen synthase kinase
A) Promoting the dephospho form of glycogen synthase
A 10-year old boy complains of muscle cramping following mild exercise. Lab tests reveal muscle enzyme deficiency and elevated muscle glycogen with normal structure. Which of the following enzymes is most probably deficient in this boy?
C) Glycogen synthase
E) Glycogen phosphorylase
E) Glycogen phosphorylase
_______ glycosidic bonds are linear and ______ glycosidic bonds are formed at the branch points of glycogen
Alpha 1,4; alpha-1,6
_________ end of glycogen consists of glucose monomer connected to glycogenin
What is the role of glycogenin at the end of the reducing end of glycogen?
Creates a short glycogen polymer on itself and serves as a primer for glycogen synthesis
Glycogen is degraded and extended from the __________ end
What are the 2 main tissue storage sites for glycogen?
Liver and muscle
How is glycogen stored?
As granules; the granules contain not only glycogen but also enzymes needed for glycogen metabolism
- Defects in these enzymes can lead to disorders
What is the role of liver glycogen?
Regulate blood glucose levels
What is the role of muscle glycogen?
Provides reservoir of glucose for physical activity
What are the 3 key steps of glycogen synthesis?
1) Trapping and activation of glucose
2) Elongation of glycogen polymer
3) Branching of glycogen chains
What are the steps of the first phase of glycogen synthesis: trapping and activation of glucose?
Glucose -> Glc-6-P with hexo/glucokinase then Glc-6-P -> Glc-1-P with phosphoglucomutase then Glc-1-P -> UDP-glucose wth UPD-glucose phosphorylase
What is the enzyme used in the second phase of glycogen synthase: elongation of glycogen primer?
**RATE LIMITING STEP**
What types of bonds does glycogen synthase form?
What is the enzyme used in the third phase of glycogen synthesis: branching of glycogen chains?
Glucosyl (4:6) transferase (branching enzyme)
What type of bonds does glucosyl (4:6) transferase make?
What is the rate limiting step of glycogenesis?
When does a glycogen polymer add a branch point?
When glycogen chain reaches about 11 residues, a 7 residue chain is broken off and reattached as a branch
What is the purpose of branching a glycogen polymer?
Branching increases solubility of glycogen and increases number of terminal non-reducing ends
What are the 2 key steps of glycogenolysis?
1) Chain shortening
2) Branch transfer and release of glucose
What are the steps of the first phase of glycogenolysis: Chain shortening?
Glycogen -> shortened glycogen chain using glycogen phosphorylase
What is the cofactor for glycogen phosphorylase?
Pyridoxal Phosphate (PLP) (Vitamin B6)
Glycogen phosphorylase cuts glycogen until it gets within how many residues of the branch point?
What are the steps of the second phase of glycogenolysis: branch transfer and release of glucose?
Debranching enzyme uses its transferase activity to transfer a block of 3 of the 4 remainnng 4 glucose to the non-reducing end of the man chain then the enzyme cleaves the alpha-1,6 bond of the single remaining glucose residue to release free glucose.
What is the Glucose-1-P to free glucose ratio created by glycogenolysis?
What is the rate limiting step of glycogenolysis?
Explain lysosomal glycogenolysis
Glycogen -> shortened glycogen using acid Maltase
In the liver, glucose-1-P is converted to glucose-6-P by ________ and then to glucose by ___________. Free glucose is released into bloodstream.
Myocytes in skeletal and cardiac muscle lack _______________ and hence cannot hydrolyze glucose-6-P, so they use it to generate energy via glycolysis and TCA cycle
Is glycogen synthase active in the dephosphorylated or phosphorylated form?
Glycogen synthase is active in the dephosphorylated form and inactive in the phosphorylated form
Is glycogen phosphorylase active in the dephosphorylated or phosphorylated form?
Glycogen phosphorylase is active in the phosphorylated form and inactive in the dephosphorylated form
What inhibits glycogenesis in the liver?
What stimulates glycogenesis in the liver?
What stimulates glycogenolysis in the liver?
What inhibits glycogenolysis in the liver?
What stimulates glycogenesis in the muscle?
What inhibits glycogenesis in the muscle?
What stimulates glycogenolysis in the muscle?
What inhibits glycogenolysis in the muscle?
What hormone does not act on the muscle?
- Muscle doesnt have receptors for glucagon however liver and muscle both contain receptors for insuliin
What GLUT receptor is not always present on the membrane and is expressed on the membrane upon demand?
What is the mechanism of action for activated glycogen synthase when insulin levels are high?
Insulin binds to receptor -> PKB turned on -> PKB phosphorylates PP1 activating it and GSK3 inactivating it -> PP1 dephosphorylates glycogen synthase activating it
What is the mechanism of action for inactivating glycogen phosphorylase in a state of high insulin?
Insulin binds to receptor -> PKB active -> PKB phosphorylates PP1 which inhibits PK and dephosphorylates glycogen phosphorylase
Mutations in insulin receptor and/or downstream signaling proteins leading to insulin resistance is characterized by what disease?
Type 2 diabetes
What is the mechanism of action for inactivating glycogen synthase in a state of high glucagon or epinephrine?
Glucagon or epinephrine binds GCPR -> GTP phosphorylates AC which causes ATP to phosphorylate cAMP which activates PKA, the PKA phosphorylates inhibitor 1 which inhibits PP1 and PKA phosphorylates glycogen synthase inactivating it
What is the mechanism of action of activating glycogen phosphorylase in a state of high glucagon or epinephrine?
Epinephrine or glucagon binds to GCPR -> GTP phosphorylates AC causing ATP to phosphorylate cAMP, then cAMP phosphorylates PKA which phosphorylates inhibitor 1 that blocks PP1, PKA also phosphorylates PK which phosphorylates glycogen phosphorylase activating it
What directly stimulates PK (used to activate glycogen phosphorylase)
Ca2+ (in muscle)
______ inhibits glycogen phosphorylase in liver but not in muscle
_____________ activates glycogen synthase and inactivates glycogen phosphorylase
_____ activates glycogen phosphorylase especially during periods of exercise.
What enzyme is defective and what pathway is affected in GSD 0?
Glycogen synthase is defective, affecting chain elongation in glycogenesis
What enzyme is defective and what pathway is affected by GSDII/Pompe disease?
Acid Maltese is defective, affecting lysosomal glycogenolysis and the release of glucose
What enzyme is defective and what pathway is affected by GSD IV/Andersen disease?
Glucosyl (4:6) transferase (branching enzyme) is defective, affecting chain branching in glycogenesis
What enzyme is defective and what pathway is affected by GSD V/McArdle disease?
Muscle glycogen phosphorylase is defective, affecting Glycose-1-P release in glycogenolysis
Wha enzyme is defective and what pathway is affected by GSD VI/Hers disease?
Liver glycogen phosphorylase, affecting Glucose-1-P release in glycogenolysis
What are symptoms of GSD 0?
Patients cant synthesize glycogen so they have muscle cramps due to lack of glycogen in muscle, rely on glucose in diet, vulnerable to hypoglycemia when fasting (during sleep) and need to eat frequently
What are the symptoms of GSD IV/Andersen disease?
Due to deficiency in branching enzyme, patients have long chain glycogen with fewer branches, causing enlargement of liver and spleen and scarring of liver tissue (cirrhosis)
(**More serious than GSD 0 -> death by 5yo)
What are the symptoms of GSDV/McArdle disease?
Patients are unable to supply muscles with enough glucose so they have weakness, muscle crams, exercise intolerance, and myoglobinuria (myoglobin in urine)
- Can test for this with urinalysis
What are the symptoms of GSD VI/Hers disease?
Prevents glycogen breakdown in liver, so it accumulates in the liver causing hepatomegaly and low blood glucose levels
What are the symptoms of GSD II/Pompe disease?
Accumulation of glycogen in lysosomes disrupting functioning of muscle and liver cells leading to progressive muscle weakness and myopathy (including hear and skeletal muscle)
- ERT - recombinant human alpha-glucosidase delivered via IV innfusion to young children and babies
- Children die of heart failure
What 3 things activate glycogen phosphorylase in the muscle?
Ca-CaM (elevated during muscle contraction)
Liver glycogen phosphorylase is inactivated by ___________ and unaffected by _____
Free glucose; AMP
Mutation in liver glycogen phosphorylase leads to _______ disease